Monoclonal antibodies for immunotherapy are a powerful weapon in the battle against human disease, but current technology is limited to monoclonals generated from mice genetically engineered to express a human sequence antibody repertoire. A major advance would be to generate polyclonal human antibodies in a phylogenetically distant animal for increased antibody performance in therapeutic applications. The biology of the chicken makes it an ideal candidate for such an animal host. The proposed research in Phase I will test whether human immunoglobulin genes can be properly processed and expressed in the context of the chicken immune system. The human heavy chain locus in its germline configuration will be introduced into chicken embryonic stem cells and chimeric chickens will be made. Chimeras will be analyzed for the production of a human heavy chain repertoire in their serum and B cells. In Phase II, the approach will be fully developed by constructing a strain of chickens containing inactivated endogenous immunoglobulin genes and copies of the human heavy and one of the light chain loci for the production of fully human antibodies. This technology will enable the production of both nomoclonal and polyclonal human sequence antibodies of higher avidity and effectiveness than now possible. PROPOSED COMMERCIAL APPLICATION: The proposed research describes technology to produce therapeutic human polyclonal antibodies in the chicken. There are large-market opportunities for human antibodies to treat a wide variety of human diseases. The proposed technology will offer several advantages over current antibody production methods and thus will easily capture a share of this market.